A Phase III, Multicentre, Double-Blind, Randomised, Placebo-Controlled Study to Confirm the Safety and Efficacy of Subcutaneous Bioresorbable Afamelanotide Implants in Patients with Erythropoietic Protoporphyria (EPP).

Erythropoietic protoporphyria (EPP) is a genetic disorder in which impaired
ferrochelatase activity results in the accumulation of its substrate,
protoporphyrin. There are two main clinical manifestations of protoporphyrin:
cutaneous phototoxicity and hepatobiliary disease. Phototoxicity is the more
common of these and it usually presents in early childhood as intolerance to
sun-exposure with patients experiencing severe burning pain in the skin most
often on the face and hands. It may last for several days and may be
accompanied by swelling and redness on sun exposed areas.

Accumulation of protoporphyrin IX in the skin is responsible for cutaneous
photosensitivity leading to (i) pain, (ii) swelling, (iii) discrete scarring
and (iv) formation of ulcers. In the presence of light at 410 nm,
protoporphyrin IX generates reactive oxygen species resulting in the typical
phototoxic reactions. Protoporphyrin IX is eliminated exclusively via the
liver. When the capacity of the biliary excretion pathway is exceeded, excess
protoporphyrin IX may result in the formation of gallstones or cholestatic
liver damage.

Available treatment modalities for patients with EPP are limited. Avoidance of
strong sunlight, either from direct exposure or through windows glass and the
use of protective clothing is essential to prevent phototoxic reactions.
Systemic β-carotene has been shown to be of benefit in the treatment of EPP
although good efficacy data are lacking. The clinical benefits of other
treatments such as PUVA, UVB, oral cysteine5, cholestyramine and the
combination thereof remain to be proven. The most effective measures are
reflecting sunscreens containing titanium dioxide.

Afamelanotide is an analogue of alpha-MSH which stimulates the production of
eumelanin in the skin without the specific cell damage that usually occurs when
melanin production is stimulated by UV radiation. Melanin, in the form of
eumelanin, is a photoprotective agent. The mechanisms proposed for
photoprotection include, but are not limited to, the absorption and scattering
of UV light, free radical scavenging and quenching of UV light. There is also
increasing evidence that melanogenesis represents a major antioxidant defense
mechanism in melanocytes, neutralising the deleterious effects of free radicals
and active oxygen species9. Eumelanin acts as a neutral density filter and,
unlike most sunscreens, reduces all wavelengths of light equally so that the
photoprotection provided by epidermal melanin pigmentation is essentially
independent of wavelength.

A pilot study of afamelanotide in EPP patients demonstrated that afamelanotide
treatment increased the *time to appearance of provoked symptoms* following
provocation with an artificial light source. An interim analysis conducted on
14 patients enrolled in a phase III study demonstrated that afamelanotide
reduced the severity of phototoxicity, demonstrated using a visual analogue
scale to measure pain intensity. The phase III study is ongoing and final data
will not be available until the end of 2009.

This study aims to extend experience with afamelanotide in EPP patients by
evaluating its effectiveness in EPP patients in a second phase III study.

Primary objective:
- To determine whether afamelanotide can reduce the severity of phototoxic
reactions in patients with EPP
Secondary objectives:
- To determine whether afamelanotide can reduce the number of phototoxic
reactions in patients with EPP
- To evaluate the safety and tolerability of afamelanotide by measuring
treatment-emergent adverse events (AEs)
- To determine whether afamelanotide can improve the quality of life of EPP
patients
- To determine the effect of afamelanotide on free protoporphyrin IX levels
- To determine whether afamelanotdie can increase the duration of sunlight
tolerated by patients with EPP and
- In a subset of patients (not in the Netherlands), determine whether
afamelanotide implants can reduce the susceptibility to provocation with a
standardized light source (minimal symptom dose (MSD) and minimal erythema dose
(MED)).

This is a randomized placebo-controlled study to be conducted in two parallel
study arms for a 9 month period (5 doses) during Spring and Summer.
Approximately 10 eligible patients per centre will be enrolled and will receive
afamelanotide (16 mg implants) or placebo according to the following dosing
regime:

- Group A will be administered afamelanotide implants on Days 0, 60, 120, 180
and 240
- Group B will be administered placebo implants on Days 0, 60, 120, 180 and 240

To determine eligibility for study inclusion, patients will undergo a screening
evaluation 7 days prior to the administration of the first dose.

Not applicable

(1) Prophylactic phototherapy will be withheld. Therefore there is a risk that
the patients may experience EPP when the summer commences. However, this
therapy is not routine for patients due to the inherent risks and the
cumulative increase in the risk of skin cancer.

(2) Adverse events (AEs) or risks associated with afamelanotide. The sustained
release implant alpha-MSH has been previously administered with mild AEs
occuring in 10 20% of subjects. These included nausea, facial flushing and
gastrointestinal discomfort experienced by 20%, 14% and 10% of subjects
respectively. These AEs were generally mild in nature and usually lasted no
more than 1 2 days. Other mild AEs which have been reported less commonly
include headache, chemical taste in the mouth, yawning, muscle twitching,
diarrhoea, light headedness and nervousness. Irregular skin tanning, darkening
of moles and freckling are also reported. (NB: Darking of moles and freckling
are not strictly AEs as they represent the natural effects of the drug. However
the rapidity of the change was such as to be recorded as an unexpected event).

(3) The active implant is a sterile biodegradable and biocompatible poly(D,L
lactide co glycolide) polymer excipient containing 16 mg of afamelanotide. The
placebo implant is identical in composition except it does not contain
afamelanotide. The implants contain no other excipients. These implants are
manufactured by Brookwood Pharmaceuticals, Birmingham, Alabama, USA.

(4) Implant procedure the main risk is discomfort and bruising at the site of
the implant. Less commonly seen side effects are infection, bleeding from the
incision site, fainting and nausea. Any patient who experiences any moderate or
severe toxicity (as judged from observed adverse events) considered related to
the drug may have the implant removed surgically otherwise the implant will
biodegrade over succeeding 2 3 months.

(5) Venepuncture the main risk is discomfort and bruising at the site of
venepuncture/cannulation. Less commonly seen side effects are infection,
bleeding from the puncture site, fainting and nausea.

(6) As there are currently no other prophylactic treatments available for
sufferers of EPP, there are no adverse effects that may occur as a result of
giving/ withholding prophylactic medication.